Abstract. Complicated parapneumonic pleural effusions (CPE) and empyema are common clinical problems which affect about 80,000 patients in the US and UK annually and are associated with mortality of about 20 percent, considerable morbidity and costs of about half a billion annually. The incidence of pleural infections is about 8-fold that of cystic fibrosis, five-fold that of idiopathic pulmonary fibrosisand mortality exceeds that of myocardial infarction or community acquired pneumonia . While surgery can be lifesaving, it is invasive and many patients are not operative candidates. Pharmacologic drainage of the pleural space is therefore desirable. Fibrinolysins such as tissue plasminogen activator (tPA) have been used with or without adjuncts but entail a significant bleeding risk and dosing is completely empiric, as all agents now used in the clinic are used off-label. Based on our publications and work done on our team's NIH-supported work over the past decade, we identified single chain urokinase plasminogen activator (scuPA) as a candidate to better and more safely achieve pleural drainage, mitigate the risk of bleeding and requirement for surgery and thereby improve outcomes while reducing costs of care for patients with CPE/empyema. This project has been embraced by study sections including NIH RAID and SMARTT, which is on schedule to manufacture scuPA under cGMP for initial clinical trial testing in patients with CPE/empyema by the second quarter of 2015. We have completed a pre-IND meeting with the FDA and IND-enabling work is now underway. To ensure that newly manufactured drug is used in clinical testing, we must now apply for support of a Phase Ia/Ib dose escalation trial of intrapleural scuPA for treatment of patients with CPE/empyema. Hypothesis: We propose that scuPA will be well- tolerated in the proposed Phase Ia/Ib clinical trial in patients with loculated CPE/empyema. Objectives: To determine the safety, pharmacokinetics, phamacodynamics and preliminarily assess efficacy of intrapleural fibrinolytic therapy (IPFT) with scuPA in patients with pleural loculation and CPE/empyema. We will conduct a phase Ia/Ib clinical trial dose escalation trial using a 3+3 design to address the hypothesis. We have 3 Specific Aims: 1) To determine safety of intrapleural scuPA delivered in escalating doses in patients with CPE/empyema. 2) To preliminarily assess efficacy parameters in patients treated with escalating doses of intrapleural scuPA and 3) To assess the processing and bioavailability of intrapleural scuPA in patients with CPE/empyema. Here, we will also assess the pharmacokinetics and pharmocodynamcs of scuPA IPFT, which is a first-in-kind analysis of any intrapleural fibrinolysin in humans. This project is of potentially great clinical importance, as reliable pharmacotherapy for CPE/empyema is now unavailable and current IPFT is used off label and empiric, leading to uncertain safety and variable efficacy. If successful, this phase Ia/Ib safety trial will inform the field and justify testing of scuPA in a randomized phase II efficacy trial that could establish this agent as the first formally vetted, FDA-approved, primary intervention for patients with loculated CPE/empyema.